Researchers from Ben-Gurion University of the Negev discovered that DNAJB12 and DNAJB14 function as part of a mechanism that is sensitive to the intensity of stress and the redox state of the cell. Under mild stress, they support an adaptive pathway, but when stress is severe and prolonged, they break down and allow activation of a pathway related to programmed cell death.
Living cells are constantly under stress. Proteins need to fold into the correct shape, damaged molecules need to be broken down, and the environmental conditions inside the cell need to be maintained within a narrow range. When the stress increases, the cell can try to adapt and repair the damage—but if the situation is too severe, it may activate a program of programmed cell death.
New research from Ben-Gurion University of the Negev reveals a mechanism that helps determine when a cell is still in a zone where it can cope with stress, and when it moves in the direction of Apoptosis.
The study, published in the journal Redox Biology, edited by Laila Abu Madigam, Noa Gabrieli, Raifu Tolulopa Adebisi, and Dr. Aide Agbariya from the Department of Life Sciences at Ben-Gurion University of the Negev.
At its center are two proteins – DNAJB12 and-DNAJB14 – located in the membrane The endoplasmic reticulum.
The protein factory that also responds to emergencies
The endoplasmic reticulum is a branched system of membranes within the cell, in which, among other things, the production, folding, and quality control of proteins intended for secretion or integration into cell membranes take place.
When proteins that are not folded properly accumulate in it, or when the conditions necessary for its work are compromised, a Endoplasmic reticulum stress.
The cell has many systems to deal with such a situation. Some temporarily reduce the protein production load, others increase the activity of repair and degradation mechanisms.
But the response cannot continue indefinitely. If the cell fails to restore the system to balance, survival mechanisms may give way to pathways that promote cell death.
In moderate stress: proteins help adapt
The researchers examined a pathway known as ERCYS, in which proteins normally found in the endoplasmic reticulum move back into the cytosol – the intracellular fluid outside the organelles.
Under moderate stress, the researchers found that this process is particularly active.
DNAJB12 and DNAJB14 play a central role in the process. Under these conditions, they are maintained in a stable state by disulfide bonds within the protein molecules.
They work together with chaperones – proteins that help other proteins fold and avoid abnormal aggregation – and support the transport of proteins from the retina to the cytosol.
This response may reduce the load on the retina and allow the cell to continue to function.
When the oppression intensifies – the picture reverses
The researchers discovered that the response does not increase as the stress increases. Quite the opposite.
When retinal strain became more severe, or when the researchers created strong reducing conditions in the cells, the amount ofגלוטתיון In the cell.
The change in the redox balance caused the disulfide bonds that stabilize DNAJB12 and DNAJB14 to break down.
As a result, the proteins became less stable and were degraded.
As their levels decrease, the pathway for transporting proteins from the retina to the cytosol also weakens.
That is, the same mechanism that supports adaptation to moderate stress stops working when the cell crosses a certain threshold of distress.
BIK recruits BAX and BAK
This is where proteins involved in apoptosis come into play.
The researchers found that DNAJB12 helps maintain low levels of the pro-apoptotic protein under normal conditions. TAURUS.
When DNAJB12 and DNAJB14 disappear, BIK becomes more stable.
BIK then helps recruit proteins BAX and-BAK to the endoplasmic reticulum membrane. These proteins can form structures in the membrane and increase its permeability – part of a chain of events linked to the activation of the cell death pathway.
In experiments in which DNAJB12 and DNAJB14 were silenced, the cells became more sensitive even to relatively low levels of retinal stress.
In contrast, when BIK was lacking, the level of apoptosis induced by several types of stress was reduced.
Not a simple on/off switch
Despite the use of the term "molecular switch", the process is not a simple binary switch.
The study describes a cascade system that is sensitive to the intensity of the pressure and the chemical environment within the cell.
In moderate stress, DNAJB12 and DNAJB14 are stable and assist in the adaptive pathway.
In severe and prolonged stress, the redox balance changes, proteins break down, and the system leans more toward a pro-apoptotic pathway.
This way, the cell can adapt its response to the severity of the situation and not just to the mere existence of stress.
The connection to cancer and degenerative diseases
The finding may be particularly relevant to diseases in which the balance between cell survival and death is disrupted.
Cancer cells often live in an environment of oxygen and nutrient deprivation and high metabolic stress, yet manage to survive.
It has already been described in the past by a scientist how Endoplasmic reticulum stress can actually aid the survival of cancer cells.
On the other hand, in degenerative diseases of the nervous system and other diseases, premature cell death may be part of the disease process.
Understanding the control points that determine whether a cell will continue to adapt or initiate apoptosis may in the future help identify therapeutic targets.
However, the current study is basic research. It does not present a cure and does not prove that the mechanism can already be controlled in humans.
The key is also in the redox state.
One of the key innovations in the research is the role of the redox balance.
The researchers found that the change in glutathione levels and the state of the disulfide bonds of DNAJB12 and DNAJB14 directly affects their stability.
Thus, the cell's chemical environment becomes a kind of internal indicator of the severity of the stress.
The finding connects protein quality control, chaperones, redox status, and cell death mechanisms – systems that were previously sometimes studied separately.
Questions and Answers
What are DNAJB12 and DNAJB14? These are auxiliary proteins from the chaperone family, which are located in the endoplasmic reticulum membrane and participate in quality control and protein movement.
What happens to them in times of great stress? Changes in the redox balance damage the bonds that stabilize them, and they undergo disintegration. As a result, the adaptive pathway they assist in is weakened.
How does this relate to cell death? When DNAJB12 and DNAJB14 are decreased, the BIK protein is stabilized and helps recruit BAX and BAK to the retinal membrane, a process linked to the activation of apoptosis.
Can the mechanism already be used to treat cancer? No. This is basic research in cells and experimental models. Further studies are needed to determine whether the mechanism can be exploited therapeutically and safely.
Scientific source: DNAJB12/14 redox switching directs chaperone- and Bax/Bak-dependent ER protein reflux – Redox Biology
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For the original publication: Opening the original publication
